IκB kinase (sometimes to be abbreviated as IKK in the specification) is a kinase complex having a molecular weight of not less than 900 kilodaltons that phosphorylates IκB. This complex includes kinase subunits such as IKKα (IKK-1), IKKβ (IKK-2), regulatory subunit IKKγ (NEMO) and the like.
IKK phosphorylates serine 312 of IRS-1, which is an insulin receptor substrate, and the like, and induces insulin resistance by inhibiting the phosphorylation of tyrosine of IRS-1 that should originally occur (J. Biol. Chem., 277, p. 48115 (2002)). Therefore, an IKK inhibitor is expected to improve insulin resistance observed in type II diabetes and obesity.
In addition, IKK is known to significantly con-tribute as one factor in the signal transduction pathway of NF-κB transcription factor. NF-κB is generally bound with inhibitory protein IκB and present as an inactive type in cytoplasm. Once IKK phosphorylates IκB, this triggers ubiquitination of IκB and degradation of IκB proceeds. NF-κB liberated by the degradation of IκB is translocated into the nucleus, where it activates transcription of the target gene and accelerates production of inflammatory cytokines such as tumor necrosis factor (TNF), IL-1 etc.; cell adhesion factors such as ICAM-1 (Intercellular Adhesion Molecule-1) etc.; and enzymes such as cyclooxygenase COX2 (Cyclooxygenase-2) and the like. In this way, NF-κB is deeply involved in inflammation and immune responses. IKK is also known to activate NF-κB by phosphorylation of NF-κB subunits and histone. Therefore, an IKK inhibitor is expected to suppress activation of NF-κB and be useful as an agent for preventing or treating autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis), inflammatory diseases (e.g., osteoarthrosis, atherosclerosis, atopic dermatitis, chronic obstructive pulmonary disease, endotoxin shock, sepsis), ischemic diseases and the like or as an immunosuppressant. Moreover, since NF-κB acts as an anti-apoptosis factor or growth factor in cancer cells, an IKK inhibitor that suppresses activation of NF-κB is expected to be useful as an agent for preventing or treating cancer (J. Clin. Invest., 107, pp. 241-246 (2001)).
In the meantime, as 6-azaindole compounds, the following compounds have been reported.
(J. Chem. Soc., Perkin 1, 1973, pp. 1546-1556)
(J. Chem. Soc., Perkin Trans. 1, 1996, pp. 2633-2642).